The present invention relates primarily to the field of biochemistry and medicine. More particularly, it is concerned with lipid-containing compositions which, in one main aspect of the invention, provide useful surfactants or solubilizing agents for certain substances, particularly drugs or other bioactive materials, and can be especially useful for producing aqueous solutions of substances that are lipid soluble but have poor aqueous solubility. Thus, they can be used as formulating and delivery agents for the formulation and/or delivery, possibly site-specific delivery, of drugs or other bioactive materials in connection with therapeutic (or cosmetic) treatment of mammals. These lipid-containing compositions also provide artificial surfactants having useful therapeutic applications in medicine, e.g. as lung surfactants or as lubricating surfactant materials for inclusion in ocular formulations or other lubricating formulations for medical use. The compositions can, however, have other uses and applications, particularly as solubilizing agents, in different areas of biochemistry or biotechnology and in the food industry for example.
There is a continual need for new or improved drug formulation and/or delivery agents, particularly for example in connection with administration of active drugs that have poor aqueous solubility. Improved drug delivery methods are also important in connection with the development of gene therapy where the drug to be administered or delivered is therapeutic genetic DNA or RNA or DNA/RNA fragments which need a carrier vehicle for protection and for facilitating take-up by target cells. Also, there is a need for improved delivery agents for achieving efficient delivery of other sensitive or unstable drugs as well as for achieving efficient delivery of drugs of poor aqueous solubility. There is moreover often a need for efficient and non-toxic solubilizing agents in other fields, for example in the food and cosmetic industries.
Also, a need has been identified for solubilising agents that can be used for solubilising proteins, especially drug receptor proteins for example within phospholipid membranes in such a way as to retain their native conformation and thereby to enable their structure to be determined e.g. by NMR spectroscopy. Elucidation of their structures in this manner may enable more efficient agents to be designed to interact with such receptors and act as potential drugs. Some embodiments of this invention may help to meet these various needs.
With regard to lung surfactants, as is well known, to achieve a proper respiratory function and gaseous exchange, all mammals secrete in their lungs a surfactant for controlling during exhalation and inhalation the surface tension of the fluid film that covers the epithelial respiratory surface lining the alveoli. The alveoli form in effect a series of minute interconnecting fluid-lined sacks, arranged so as to maximize the surface area for gaseous exchange across a fluid/air interface. However, this arrangement presents a potential physico-chemical problem for the body in that the alveoli sacks approximate in form to small bubbles subject to Laplace""s law whereby the gaseous pressure within the bubble is inversely proportional to the radius or diameter and is directly proportional to the surface tension of the fluid in the boundary film. Thus, as the diameter of an alveolar sack decreases during exhalation, the pressure therein will tend to increase and this could lead to pressure disparities. Pressure disparities between the alveoli, however, would tend to force air from the smaller alveolar sacks into the larger ones, resulting in a collapse of the former. If this situation occurred in vivo subsequent expansion of the lungs would be far more difficult and the entire lungs may even collapse.
To avoid these problems mammals produce a natural surfactant to lower the surface tension of the fluid film of the alveolar surfaces when the surface area is constricted during exhalation. Conversely, the force needed to inflate the lungs is also equalised. In both cases the lungs are able to deflate and inflate uniformly with a variation in terminal size of different alveoli. Such a degree of functional control is achieved by reducing surface tension in direct proportion to the reduction in surface area and this, in turn, is achieved by an increase in the concentration of surfactant per unit area at the surface. The mechanism is similar to that employed in a Langmuir trough, whereby constriction of an insoluble monolayer squeezes water out of the interface so minimizing the cohesive forces between water molecules acting to xe2x80x98pullxe2x80x99 the surface together.
In human neonates, lung surfactant is synthesized around two months prior to term, enabling the lungs to inflate and normal breathing to commence at birth. However, in infants born more than two months premature the quantities of lung surfactant may be greatly reduced or completely absent and this situation prevents the lungs from inflating, resulting in the development of neonatal respiratory distress syndrome (RDS) which remains the most common cause of neonatal mortality.
Endogenous lung surfactant generally consists of 90% (wt./vol.) lipid in combination with 10% protein. The lipoidal fraction is made up of 90% phospholipid of which 80% is phosphatidylcholine (PC), with some 40-45% in the form of the dipalmitoyl ester (DPPC) and the remainder as monoenoic PC. The lipid usually also contains 10-15% phosphatidylglycerol (PG) and 7-8% cholesterol.
In early attempts to develop artificial phospholipid-based surfactants using only phospholipids, or lipoidal mixtures simulating the lipid composition of native lung surfactant, it was found that such artificial surfactants were significantly less effective than the natural product in treating RDS. In particular, it was found that the phospholipids used often failed to completely adsorb and spread at the alveolar air/fluid interface in the absence of certain apoproteins, termed surfactant proteins, which occur in endogeneous surfactant. It is believed that these surfactant proteins act to modify the assembly of phospholipids and transport the latter from T cells lining each alveolus across the aqueous subphase to form a lipid monolayer at the air interface.
This difficulty has been partly overcome by the recent introduction into clinical practice of artificial lung surfactants for treatment of RDS based upon animal derived apoprotein extracts (see Table of Commercial Surfactants below and also Table I at the end of the present description). However, although this development has revolutionized treatment of this disorder, it can result in dramatic cost increases being imposed on health care providers as these known artificial lung surfactants are generally very costly, and also they pose serious questions as to the suitability of using animal proteins in treatment of human neonates.
There is accordingly a need for an effective artificial lung surfactant that can be manufactured cheaply from synthetic materials, and the provision of such an artificial surfactant represents one object of the present invention. It will be appreciated that the implications of this work in developing an effective and cheap artificial lung surfactant may have far reaching consequences in terms of the numbers of individuals that could benefit. A conservative estimate of the mortality rate arising from respiratory distress syndrome (RDS) would suggest, based upon published statistics (xe2x80x9cInfant mortality ratesxe2x80x9d from US Dept. Health and Human Services, 1992), that globally there are some 100,000 cases per annum, mainly in developing countries. Hence, a cheaply available lung surfactant may significantly influence both the survival rate and subsequent health of a considerable number of children world-wide.
Apart from a need for artificial lung surfactants, pharmaceutically acceptable surfactants are also needed for treatment of other medical conditions affecting membraneous or mucosal surfaces, e.g. tear film surfactants for ocular use in treatment of the condition known as xe2x80x9cdry eyexe2x80x9d syndrome, and surfactants for lubricating or treating the surfaces of articulated joints in connection with arthritic conditions. There is also a need for lubricating surfactants to lubricate surfaces of medical devices and prostheses, e.g. artificial joints and contact lenses, that are fitted in the human or animal body.
From one aspect the present invention provides a lipid-containing composition which consists of a substantially clear aqueous solution containing a membrane-forming polar lipid and a synthetic amphipathic polymer, said polymer including both hydrophobic groups and anionic hydrophilic groups and acting as a lipid-solubilizing agent which interacts with and solubilizes the lipid in the aqueous medium. In many embodiments the lipid-containing compositions of this invention will be used or formulated for use in therapy. Thus, from another aspect the invention also resides in the use of a lipid-containing composition for the manufacture of a medical preparation, said composition consisting of a substantially clear aqueous solution containing a membrane-forming polar lipid and a synthetic amphipathic polymer, said polymer including both hydrophobic groups and anionic hydrophilic groups and acting as a lipid-solubilizing agent which interacts with and solubilizes the lipid in the aqueous medium.
From another aspect the invention also provides a lipid-containing composition consisting of a substantially clear aqueous solution containing a membrane-forming polar lipid together with a synthetic amphipathic polymer and a lipid-soluble target substance of poor aqueous solubility, said polymer including both anionic hydrophilic groups and hydrophobic groups and acting as a lipid solubilizing agent which interacts with and solubilizes the lipid together with said target substance in said aqueous medium. In this case the additional lipid-soluble target substance may be present either to be delivered, (e.g. drug delivery) or, in the case of a lipid-soluble protein, to assist in the targeting of the lipid/polymer combination to particular tissues within the body, or in some cases to hold the protein in a correct confirmation for analysis.
In preferred embodiments the lipid will usually comprise a phospholipid and the synthetic amphipathic polymer with which it is combined will have a balance of hydrophobic and anionic hydrophilic groups evenly arranged along a linear backbone.
An example of one lipid-solubilizing synthetic amphipathic polymer including both hydrophobic groups and anionic hydrophilic groups which can be used in carrying out the invention is the homopolymer poly(2-ethyl acrylic acid) (PEAA) that has previously been reported as interacting in aqueous solutions at pH  greater than 7 with phosphatidylcholines such as dilauroylphosphatidyicholine (DLPC) and dipalmitoylphosphatidylcholine (DPPC) to yield suspensions of multilamellar vesicles which clear when the pH is lowered below a critical value of approximately 6.5. See for example K. Seki et al. (1984) xe2x80x9cpH-Dependent Complexation of Poly(acrylic acid) Derivatives with Phospholipid Vesicle Membranesxe2x80x9d, Macromolecules, 17, 1692-1698, D. A. Tirrell et al. (1985) xe2x80x9cpH Sensitisation of Phospholipid Vesicles via Complexation with Synthetic Poly(carboxylic acid)sxe2x80x9d, Ann. N.Y. Acad. Sci 446, 237-248, and K. A. Borden et al. (1987) xe2x80x9cPolyelectrolyte adsorption induces a vesicle-to-micelle transition in aqueous dispersions of dipalmitoylphosphatidylcholinexe2x80x9d, Polymer Preprinits, 28, 284-285).
The solubilization effect described in the literature referred to was attributed to a break-up and reorganisation of the vesicle structures accompanying conformational changes occurring in the polymer upon lowering of the pH, leading to the formation of lipid/polymer complexes producing small micellar discoidal particles or assemblies. Suggestions were also made in the above-mentioned papers that the materials described could have useful medical applications if they are prepared so that therapeutic substances are entrapped within the vesicles because upon administering such preparations in the course of medical treatment these vesicles, known as liposomes, would break up and quickly release their contents upon entering a target region of low pH. It should be noted, however, that these proposals related only to the use of compositions comprising intact vesicles or liposomes within the interior of which an aqueous soluble drug or other therapeutic agent is entrapped, the vesicles or liposomes themselves being used merely as mechanical containers. No recognition was expressed of any value, for therapeutic purposes or otherwise, of the lipid/polymer complexes of the micellar particles or assemblies produced after the break-up of the liposomes. It has now been appreciated, however, that such lipid/polymer complexes can in themselves provide useful compositions having regard to advantageous surface activity and/or solubilizing characteristics, combined with favourable small dimensional characteristics. It is these hitherto unrecognised properties and practical applications thereof which are exploited in the present invention.
The term xe2x80x9cmembrane-forming polar lipidxe2x80x9d is used herein to denote lipids having a highly polar head portion attached to a nonpolar hydrophobic tail, generally composed of a pair of relatively long hydrocarbon chains, such that in aqueous media the lipid molecules tend to associate and form membrane structures at interfaces, possibly as lipid monolayers or bilayers.
In preferred embodiments these polar lipids used in connection with the invention will usually be phospholipids based on glycerol in the form of phosphatidic acid derivatives in which the non-polar acyl ester groups contain between 8 and 25 carbon atoms. These acyl ester groups, however, are preferably selected from lauryl, palmitoyl and myristoyl, and the polar head of the molecule will be provided by the phosphate group with a choline substituent, i.e. the lipid will be a phosphatidylcholine. Nevertheless, it is also possible in some embodiments to use other polar lipids, especially phospholipids, based on different structures, for example sphingosine or a ceramide from which may be derived the phospholipid sphingomyelin.
It should be pointed out that many of these polar lipids, especially phospholipids such as phosphatidylcholines, undergo phase transitional changes in aqueous media at predetermined temperatures at which they may change from a relatively ordered to a relatively disordered state. Dipalmitoylphosphatidylcholine (DPPC), for example, has a main thermal phase transition temperature (Tm) of around 42xc2x0 C., although for dilauroylphosphatidylcholine (DLPC) the main thermal phase transition temperature is about xe2x88x922xc2x0 C. so that it is in a disordered bilayer or liquid crystalline phase at room temperature.
In carrying out the invention, instead of PEAA other similar vinyl homopolymers of an acrylic acid derivative having a hydrophobic side chain, e.g. 2-propyl acrylic acid, or other poly(carboxylic acid) polymers having pendant hydrophobic side groups in addition to anionic hydrophilic groups, may be used. In preferred embodiments, however, the selected synthetic lipid-solubilizing amphipathic polymer will be a linear alternating vinyl copolymer formed by free radical addition polymerisation of an unsaturated dicarboxylic acid, or an anhydride or monoester of said dicarboxylic acid, with a monoenoic vinyl monomer or monomers in alternating relationship.
Thus, from another aspect the invention provides a lipid-containing composition consisting of a substantially clear aqueous solution containing a membrane-forming polar lipid and a synthetic amphipathic polymer, said polymer including both anionic hydrophilic groups and hydrophobic groups and acting as a lipid-solubilizing agent which interacts with and solubilizes the lipid in the aqueous medium, characterised in that the synthetic amphipathic polymer is a copolymer of a first monomer which is an unsaturated dicarboxylic acid, or an anhydride or monoester thereof, and a second monomer which is a monoenoic compound such as a vinyl compound or a compound such as indene or napthalene, said first and second monomers being arranged in alternating relationship to form a linear backbone.
The monoenoic monomer or monomers will generally be selected from indene or napthalene and compounds of formula Rxe2x80x94CHxe2x95x90CH2 where R is hydrogen, C1-C8 alkyl or alkoxy, or is phenyl or benzyl which may be optionally substituted with an alkyl or other hydrophobic group, with the proviso that if R is alkoxy, i.e. if the compound is an alkyl vinyl ether, C3-C6 alkoxy is preferred. With regard to the dicarboxylic acid, that provides said first monomer, this will generally be a compound of formula: 
where R1 and R2 are each independently hydrogen or C1-C9 alkyl, at least one of R3 and R4 is hydrogen and the other is hydrogen or C2-C9 alkyl, and the copolymer structure is such that the second monomer units alternate with the dicarboxylic acid or ester units providing a regular arrangement of alternate pendant anionic hydrophilic side groups and hydrophobic side groups along a linear backbone, subject to the proviso that if, in the above-defined monoenoic vinyl monomer, R is hydrogen or is methoxy or ethoxy (C1 or C2 alkoxy), R3 and R4 should not then both be hydrogen. Usually, in preferred embodiments, R1 and R2 are both hydrogen, and also alkyl vinyl ether monomer-containing copolymers with alkyl groups longer than seven carbon atoms will not be suitable because of low aqueous solubility. As indicated, the dicarboxylic acid may be presented in the form of its anhydride.
Also, at least in preferred embodiments, the number of carbon atoms in the hydrophobic side groups of the polymer or copolymer should usually be equal to or greater than the number of carbon atoms in the backbone of the polymer, and when ionized the average charge ratio per backbone carbon is less than or equal to unity.
Especially suitable polymers may be formed as alternating copolymers of maleic acid (or the anhydride thereof) with styrene, indene or a C1-4 alkyl, e.g. methyl, substituted styrene or indene, or with propyl (or isopropyl) or butyl vinyl ether. It is also possible to use a mixture of the styrene, or indene, or alkylated styrene or indene, and alkyl vinyl ether components. A number of suitable copolymers that may be used are commercially available from Aldrich Chemical Co., e.g. those marketed under the Aldrich Chemical Co. catalogue number 43,529-5 (CAS Registry No. 25736-61-2). Pharmaceutical grade polymers or copolymers that can be used are available from Kuraray Co. Ltd. of Japan.
In preferred embodiments, the polymer will have physiologically or pharmaceutically acceptable non-toxic properties, and the molecular weight (number average) or relative mass of the polymer will generally be within the range of 2,000 to 20,000 daltons. In some cases, however, unless the composition is to be formulated for parenteral injection the molecular weight may be higher, e.g. up is 500,000 daltons, although usually the molecular weight will not be greater than 100,000 daltons, and will preferably be no greater than 50,000 daltons as for example with poly(maleic anhydride-butyl vinyl ether) that has a number average molecular weight equal to 43 kDa approximately. The polymer must not, however, be in the form of a xe2x80x9cblock copolymerxe2x80x9d.
Examples of typical number average molecular weights of the polymers used in carrying out this invention, especially for solubilizing drugs, are as follows:
The particular synthetic method used in synthesising the maleic anhydride styrene copolymers described herein involves a step of quenching the reaction mixture after a certain interval and favours the formation of alternating copolymers which is an essential feature in the formation of a coil with an amphipathic character such that one facet is hydrophobic and one is hydrophilic. This cannot generally be achieved in copolymers which are xe2x80x98blockyxe2x80x99 or produced by other means, e.g. in the poly(maleic anhydride-styrene) copolymers supplied by Sigma Chemical Co. St. Louis, Mo. and sold as 50% styrene (number average molecular weight 350,000), or those sold by Scientific Polymer Products Inc. Ontario, N.Y. as 50/50 maleic anhydride-styrene copolymers with a molecular weight of 50,000.
In many cases, especially for pharmaceutical applications, poly(maleic anhydride-styrene) (PMAS) will be a preferred polymer. This polymer, of molecular weight 14,000 daltons, is disclosed in U.S. Pat. No. 4,732,933 (Yamanouchi) and is already used in an approved pharmaceutical preparation conjugated to the proteinaceous antitumor agent neocarzinostatin, the polymer there acting to raise both the molecular weight and lipophilicity so leading to accumulation of the drug in certain target tissues. This polymer drug conjugate is known as SMANCS. For drug delivery, non-degradable vinyl-based polymers such as PMAS offer a potential advantage over synthetic polypeptides of analogous or identical structure to apoproteins in that they will not be rapidly hydrolysed in the blood plasma, and hence will be more likely to deliver any drug to the target site before degradation of the micelle and loss of its contents. In addition, they lack the allergic or pharmacological potential of non-native peptides or proteins.
It is believed that in aqueous media, at least over a particular pH range, the solubilizing synthetic amphipathic polymers specified will generally adopt a helical coil configuration with the hydrophobic side groups presented along one facet and the anionic hydrophilic groups presented along the opposite facet, and that they interact with the lipid in the aqueous medium to form discoidal micellar particles or assemblies of sub-liposomal dimensions in which the lipid forms a bilayer core. In any event. it has been found that these micellar particles or assemblies in the compositions of the present invention, at least when freshly prepared, have a maximum diameter or cross-sectional dimension of less than 50 nm under physiological conditions of temperature and pH. Sizes of the discoidal micellar assemblies usually appear to be in the range of 10-40 nm in diameter, typically 20 nm, and 5-7 nm thick. This compares favourably with the dimensions of lipoprotein micellar assemblies found in nature, such as the well characterized system between apolipophorin III and dimyristoylphosphatidylcholine (DMPC) that has been identified in insects, where the micelles are reported to have a diameter of 18.5+/xe2x88x922.0 nm and a thickness of 4.8+/xe2x88x920.8 nm (see Wientzek, M., Kay, C. M., Oikawa, K. and Ryan, R. O (1994), xe2x80x9cBinding of Insect Apolipophorin III to Dimyristoylphosphatidylcholine Vesicles.xe2x80x9d J. Biological Chem. 269 (6). 4605-4612). In comparison, typical phospholipid-containing liposomes currently used in drug delivery systems have a diameter of 50-100 nm for unilamellar vesicles and 400-3500 nm for multilamellar vesicles.
The compositions in accordance with the invention will generally be prepared by mixing the polymer and the polar lipid in the aqueous medium and adjusting the pH to effect solubilization. Then, particularly if required for administration to a mammal and for medical use, the pH will usually be further adjusted to a physiologically acceptable value.
Accordingly, from yet a further aspect the invention provides a method of preparing a lipid-containing composition as hereinbefore specified which comprises the steps of mixing the constituents together in an aqueous medium at a pH above a critical solubilizing value thereby to form a cloudy or turbid aqueous dispersion, and then treating the mixture with an acidifying agent to lower the pH below said critical solubilizing value whilst the temperature is above a predetermined phase transition temperature characteristic of the lipid, thereby enabling the synthetic amphipathic polymer to carry out its function as a solubilizing agent and causing the dispersion to clarify.
The invention also provides a method of solubilizing in an aqueous medium a lipid-soluble target substance that has poor aqueous solubility, said method comprising the steps of mixing together in said aqueous medium the said target substance, a membrane-forming polar lipid, and a synthetic amphipathic polymer, at a pH above a critical solubilizing value thereby to form a cloudy or turbid aqueous dispersion, and then treating the mixture with an acidifying agent to lower the pH below said critical solubilizine value whilst the temperature is above a predetermined phase transition temperature characteristic of the lipid, whereby said synthetic amphipathic polymer, which includes both anionic hydrophilic groups and hydrophobic groups, interacts with and solubilizies said lipid together with said target substance in the aqueous medium.
Also, according to the invention, a method of preparing a lipid-containing composition comprises the steps of mixing together in an aqueous medium a membrane-forming polar lipid and a synthetic amphipathic polymer at a pH above a critical lipid-solubilizing value thereby to form a cloudy or turbid aqueous dispersion, and then treating the mixture with an acidifying agent to lower the pH below said critical lipid-solubilizing value whilst the temperature is above a predetermined phase transition temperature, e.g. greater than 25xc2x0 C., which is characteristic of the lipid, whereby said synthetic amphipathic polymer interacts with and solubilizies said lipid so as to clarify the dispersion, characterised in that after the dispersion clears the temperature is reduced below said phase transition temperature to stabilise the solution, followed by the step of treating the solution with an alkaline reagent to raise the pH and adjust it to a final value above said critical lipid-solubilizing value.
In general, before use the lipid-containing compositions of the present invention will be incorporated in formulations made up to suit the particular purpose and manner of use, or mode of administration in the case of pharmaceutical applications. For making up formulations for pharmaceutical use, the lipid-containing compositions may be mixed with one or more pharmaceutically acceptable carriers, additives, diluents or excipients, and optionally with any other therapeutic ingredients desired. Such formulations may be prepared by any of the methods well known in the art of pharmacy, and may be designed for inhalation, topical or parenteral (including intravenous, intra-articular, intramuscular and subcutaneous) administration for example. Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations that, for intravenous injection, are preferably isotonic with the blood of the recipient. Thus, the invention also includes pharmaceutical formulations comprising compositions of lipid/polymer complexes as herein disclosed.
It will also be understood that the lipid-containing compositions of the present invention may be converted into alternative forms, e.g. for storage and transport, and in particular the compositions may be converted into a freeze-dried state, either before or after being incorporated into a pharmaceutical or other formulation, from which they can be reconstituted, if necessary, when required for use. All such alternative forms are to be regarded as falling within the scope of the invention.
As already indicated, particularly important applications of the invention related to advantageous surface active characteristics of the lipid-containing compositions described lie in the provision of lung surfactant formulations for use in treatment of respiratory distress syndrome (RDS), and in the provision of ocular formulations e.g. for treatment of dry eye syndrome.
Other important applications of the invention related to the advantageous solubilizing properties of the lipid/polymer complexes include the use of the compositions for drug delivery purposes. In this case the polar lipid component is preferably a phospholipid and contains a lipid soluble drug, e.g. a steroid, or other bioactive therapeutic agent, e.g. a DNA-containing vector or plasmid for gene therapy, whereby the polymer/phospholipid complex is adapted for use as a drug delivery vehicle;
In relation to the proposed use of the compositions as lung surfactants, it may be, noted that for some time synthetic polymers have been sought having secondary structures analogous to those of the native lung surfactant apoproteins in order to mimic the lipid/protein interactions found with the latter. It is surprising, however, that although a number of polymers with similar structural elements have been synthesised, these have failed to show functional behaviour analogous to those of the native target apoproteins, but on the other hand some relatively simple copolymers such as are described in connection with the present invention and which have no apparent structural similarity have been found to perform functionally in a manner that closely resembles that of the native apoproteins.
Recently a fairly clear view has emerged regarding the macromolecular structure of native lung surfactant, and the active components thereof have been identified as a bilayer structure consisting mainly of the phospholipid, dipalmitoylphosphatidylcholine (DPPC), in association with two principal apoproteins termed SP-B and SP-C which appear to be involved in spreading of the lipid at the air/fluid interface.
Of these two apoproteins, multi-dimensional NMR analysis has revealed SP-C as having a secondary structure in the form of a transmembrane coil which is dipalmitoylated at one end and spans the phospholipid bilayer with the dipalmitoyl chains projecting outwards such as to render the surface hydrophobic. On the other hand, it is believed that apoprotein SP-B forms an amphipathic coil analogous to the coiled structures found in serum lipoproteins and surrounds discoidal segments or micelles of the phospholipid bilayer in the form of a hydrophilic annulus. The arrangement envisaged is similar to the now well established arrangement described by Ryan, R. O. xe2x80x9cStructural studies of lipoproteins and their apolipoprotein componentsxe2x80x9d, Biochem. Cell Biol. 74, 155-164 (1996) in connection with certain plasma lipoproteins, illustrated in FIG. 1 of the accompanying drawing.
In developing the compositions of the present invention for use as a lung surfactant the polar lipid, generally a phospholipid, may be advantageously associated also with an additional synthetic polymer, a synthetic amphipathic polyamide polymer, that is adapted to simulate the transmembrane apoprotein known as SP-C of natural endogenous lung surfactant. Such additional polyamide polymer may be poly(lysine ethyl ester adipamide) (PLETESA) which has a coiled configuration that changes according to whether it is in a polar or non-polar medium.
When the compositions are intended for use as lung surfactants, the inclusion of additional hydrophobic esters designed to span or extend through the lipid bilayer in a manner somewhat analogous to the SP-C apoprotein of natural lung surfactant may be advantageous for assisting orientation at air/fluid interfaces of the lipid/polymer complexes of these compositions. A fatty acid ester, e.g. lauric acid lauryl ester, can be used for this purpose.